Allogeneic hematopoietic cell transplantation (HCT) for treatment of hematological malignancies frequently fails because of disease recurrence. Attempts at intensifying the preparative regimen have been limited by associated toxicities due to the non-specific nature of most conditioning agents. The overall goal of Project 1 is to overcome this limitation by delivering targeted therapy to sites of leukemic involvement to decrease the risk of relapse after HCT without increased toxicity. We have shown that [131]l-anti-CD45 antibody (Ab; BCS) can deliver targeted radiation to hematopoietic tissues, with 2-3 times more radiation delivered to marrow, up to 12 times more to spleen, and 2- 8 times more to lymph nodes than to liver, lung or kidney. This observation has been translated to human studies that demonstrated the feasibility of combining [131]I- BC8 Ab with a reduced-intensity preparative regimen of fludarabine (FLU) and total body irradiation (TBI) in patients with advanced acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). We now propose three specific aims to extend these preliminary observations. In Aim 1 we will perform a phase II study to define the efficacy of using [131]l-BC8 Ab combined with FLU and TBI in older patients with AML in remission. In Aim 2 we will extend this approach to patients lacking HLA-matched donors by determining the maximally tolerated dose (MTD) of radiation delivered by [131]l-BC8 Ab that can be combined with a haplo-identical HCT strategy employing 2 Gy TBI, FLU, and cyclophosphamide. We will then conduct a phase II study of haplo-identical transplantation in order to estimate the efficacy of this regimen. In Aim 3, we will build on our single-center experience by performing a multi-center phase I study to estimate the MTD of radiation that can be delivered via [90]Y-BC8 Ab when combined with FLU and 2 Gy TBI as a preparative regimen for older patients with advanced myeloid malignancies, and to determine the feasibility of exporting such a regimen to other institutions. We anticipate that these studies will eventually allow us to carry out definitive Phase III studies in which allogeneic HCT approaches employing [131]I- or [90]Y-BC8 Ab are compared to standard reduced-intensity and haplo-identical HCT methods. We are optimistic that these interventions will enhance the prognosis for patients with acute leukemias and myelodysplasia by increasing the response and survival rates, while minimizing toxicities.